Understanding T cell recognition of antigen and the restriction of the process by major histocompatibility complex (MHC) encoded antigens has been an important goal in immunology. A major step forward occurred with the immunochemical identification of clone specific disulfide-linked heterodimers on T cells, composed of subunits termed T cell antigen receptors (TCR) .alpha. and .beta.. The .alpha. and .beta.TCR subunits have a relative molecular mass (M.sub.r) of approximately 50,000 and 40,000 daltons, respectively (Allison et al., 1982, Immunol. 129:2293-2300; Meuer et al., 1983, J. Exp. Med. 157:705-719; Haskins et al., 1983, J. Exp. Med. 157:1149-1169). Genes that rearrange during T cell ontogeny and encode the .beta.TCR (Yanagi et al., 1984, Nature 308:145-149; Hedrick et al., 1984, Nature 308:153-158) and .alpha.TCR (Chien et al., 1984, Nature 312:31-35; Scito et al., 1984, Nature 312:36-40, Sim et al., 1984, Nature 312:771-775) subunits were isolated either by subtractive hybridization or by probing with oligonucleotides.
A unique feature of the human .alpha.,.beta.TCR was the observed comodulation (Meuer et al., 1983, J. Exp. Med. 157:705-719), coimmunoprecipitation (described in copending application Serial No. 882,100 filed Jul. 7, 1986, which is incorporated by reference in its entirety; Oettgen, et al., 1984, J. Biol. Chem. 259:12,039-12,048) and required coexpression (Weiss et al., 1984, J. Exp. Med. 160:1284-1299) of the .alpha.,.beta.TCR molecules with the T3 glycoprotein, which suggested that these two structures were related. Subsequently, the direct physical association of the two protein complexes was demonstrated by chemically cross-linking the .alpha.,.beta.TCR molecules to the T3 glycoprotein and identifying the components of the cross-linked complex as the TCR subunit and the T3 glycoprotein (M.sub.r 28,000) subunit (Brenner et al., 1985, Cell 40:183-190). A T3 counterpart is similarly associated with murine .alpha.,.beta.TCR (Allison et al., 1985, Nature 314:107-109; Samelson et al., 1984, Immunol. Rev. 81:131-144).
A third gene that rearranges in T cells, designated .gamma.TCR, has been identified in mouse (Saito et al., 1984, Nature 309:757-762; Kranz et al., 1985, Nature 313:752-755; Hayday et al., 1985, Cell 40:259-269) and in man (Lefranc et al., 1985, Nature 316:464-466; Murre et al., 1985, Nature 316:549-552). However, there are major differences between the human and mouse .gamma.TCR gene in terms of its genetic structure; for example, the cDNA of a human C.gamma.2 gene indicates five potential sites for N-linked glycosylation in the .gamma.TCR gene product, which contrasts with the notable absence of such sites in certain murine .gamma.TCR gene sequences. Thus, certain human .gamma.TCR gene products have a higher molecular weight than that of certain murine TCR.gamma. proteins.
The .gamma.TCR gene rearrangements occur in lymphocytes with suppressor-cytotoxic as well as helper phenotypes and may produce a large number of .gamma.TCR chains (Lefranc et al., 1985, Nature 316:464-466; Murre et al., 1985, Nature 316:549-552; Quertermous et al., 1986, Science 231:252-255; LeFranc et al., 1986, Cell 45:237-246, Iwamoto et al., 1986, J. Exp. Med. 163:1203-1212; Zauderer et al., 1986, J. Exp. Med. 163:1314-1318). However, the function of the .gamma.TCR gene is unknown. Furthermore, neither the protein encoded by the .gamma.TCR gene nor its possible association with other structures (as ogccurs with .alpha.,.beta.TCR and T3 glycoproteins) have been defined. In humans, the multiple glycosylation sites render it impossible to predict with accuracy the nature and size of the .gamma.TCR polypeptide structure. Additionally, the published literature does not teach or suggest the utility of .gamma.TCR with regard to diagnosing, monitoring or staging human diseases.
It appears increasingly likely that the .alpha.,.beta.TCR molecule alone determines both antigen recognition and MHC restriction on at least some T cells (Yague et al., 1985, Cell 42:81-87; Dembic et al., 1986, Nature 320:232-238). However, it is not clear that .alpha.,.beta.TCR accounts for the process of T cell selection during T cell ontogeny or for all antigen specific recognition by mature T cells. For example, suppressor T lymphocytes remain an enigma; in some cases they delete or fail to rearrange TCR genes (Hedrick et al., 1985, Proc. Natl. Acad. Sci. U.S.A. 82:531-535; Blanckmeister et al., 1985, J. Exp. Med. 162:851-863). Thus, it is of great importance to determine if a second TCR exists, to define its structure (particularly with regard to the possible use of the .gamma.TCR gene product) and ultimately to understand what function or functions it serves.